Simulated hyperglycemia impairs insulin signaling in endothelial cells through a hyperosmolar mechanism

Madonna, Rosalinda; Pieragostino, Damiana; Rossi, Cláudia; Confalone, Pamela; Cicalini, Ilaria; Minnucci, Ilaria; Zucchelli, Mirco; Boccio, Piero Del; Caterina, Raffaele De

doi:10.1016/j.vph.2020.106678

Cited by 17 publications

(8 citation statements)

References 25 publications

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“…NaCl‐induced hyperosmotic stress in noncancer eukaryotic cells yields on average a lower hydration state of differentially expressed proteins (Figure 2C and Table 2). High‐glucose media, which are often used to model the effects of hyperglycemia in diabetes and are also recognized for generating hyperosmotic conditions 62, produce an even larger average decrease in hydration state of proteins (Table 2). The larger effect of glucose than NaCl is reflected in bacterial transcriptomic and proteomic studies that show lower

Δ n_{{normalH}_{2} O}

for many organic solutes compared to NaCl 19.…”

Section: Discussionmentioning

confidence: 99%

Water as a reactant in the differential expression of proteins in cancer

Dick

2021

Comp Sys Onco

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Introduction. How proteomes differ between normal tissue and tumor microenvironments is an important question for cancer biochemistry. Methods. More than 250 datasets for differentially expressed (up‐ and downregulated) proteins compiled from the literature were analyzed to calculate the stoichiometric hydration state, which represents the number of water molecules in theoretical mass‐balance reactions to form the proteins from a set of basis species. Results. The analysis shows increased stoichiometric hydration state of differentially expressed proteins in cancer compared to normal tissue. In contrast, experiments with different cell types grown in 3D compared to monolayer culture, or exposed to hyperosmotic conditions under high salt or high glucose, cause proteomes to “dry out” as measured by decreased stoichiometric hydration state of the differentially expressed proteins. Conclusion. These findings reveal a basic physicochemical link between proteome composition and water content, which is elevated in many tumors and proliferating cells.

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Δ n_{{normalH}_{2} O}

for many organic solutes compared to NaCl 19.…”

Section: Discussionmentioning

confidence: 99%

Water as a reactant in the differential expression of proteins in cancer

Dick

2021

Comp Sys Onco

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“…Attenuated insulin signalling can also result from changes in insulin resistance and/or post-receptor signalling. 18 We show here that exposure to HG affects the total amount of IR-α and IRS-1 levels, with the hyperosmolar component starting to act on the signal further downstream of the IRS-1. Overall, this indicates that the altered CSC responsiveness to insulin is due to a disturbance in the signalling pathway starting from IR-α ( Figure 6).…”

Section: Discussionmentioning

confidence: 65%

“…Since these effects are observed only in the PI3K/Akt pathway, while in the same conditions CSC do not lose the ability to respond to insulin with the activation of P38, these data support the hypothesis that HG promotes an imbalance in CSC insulin signalling between pro‐survival and pro‐inflammatory arms, with insulin preserving its signalling capacity through the mitogenic and pro‐inflammatory arm. Attenuated insulin signalling can also result from changes in insulin resistance and/or post‐receptor signalling 18 . We show here that exposure to HG affects the total amount of IR‐α and IRS‐1 levels, with the hyperosmolar component starting to act on the signal further downstream of the IRS‐1.…”

Section: Discussionmentioning

confidence: 74%

“…17 We have recently shown that HG impairs the PI3K/Akt/eNOS pathway and shifts insulin signalling towards the activation of mitogenic and pro-inflammatory effectors, such as p38 and ERK1/2. 18 Here, we investigated the effects of HG and HM in phosphorylation of the pro-survival marker Akt and the pro-inflammatory marker p38 in CSC. In HG and HM, the levels of Ser473-phosphorylated Akt in CSC were reduced (Figure 2A).…”

Section: Empagliflozin Increases the Expression Of Phosphorylated Amentioning

confidence: 99%

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Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes

Madonna

Doria

Minnucci

et al. 2020

J Cellular Molecular Medi

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Heart failure (HF), with or without ischaemic heart disease, remains the leading causes of death worldwide. 1 This can be attributed at least in part to the inability of the heart to regenerate damaged tissue. 2 As a result, the lost myocardium is replaced with fibrosis, initiating a series of subsequent events that lead to adverse ventricular remodelling and organ failure. 3 Cardiac stromal cells (CSC) are a heterogeneous population of non-cardiomyocyte CD45-, CD34-, CD31-and CD105+ cells including fibroblasts, resident in the heart

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“…This may contribute to insulin resistance. The mechanism involves AQP1 and the transcription factor Ton/EBP (NFAT5) for osmosensing, and the effect can be reversed by silencing the transcription of these proteins ( Madonna et al, 2020 ).…”

Section: Water Ions and Their Channels And Transporters In Pinocytosismentioning

confidence: 99%

From Pinocytosis to Methuosis—Fluid Consumption as a Risk Factor for Cell Death

Ritter

Bresgen

Kerschbaum

2021

Front. Cell Dev. Biol.

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The volumes of a cell [cell volume (CV)] and its organelles are adjusted by osmoregulatory processes. During pinocytosis, extracellular fluid volume equivalent to its CV is incorporated within an hour and membrane area equivalent to the cell’s surface within 30 min. Since neither fluid uptake nor membrane consumption leads to swelling or shrinkage, cells must be equipped with potent volume regulatory mechanisms. Normally, cells respond to outwardly or inwardly directed osmotic gradients by a volume decrease and increase, respectively, i.e., they shrink or swell but then try to recover their CV. However, when a cell death (CD) pathway is triggered, CV persistently decreases in isotonic conditions in apoptosis and it increases in necrosis. One type of CD associated with cell swelling is due to a dysfunctional pinocytosis. Methuosis, a non-apoptotic CD phenotype, occurs when cells accumulate too much fluid by macropinocytosis. In contrast to functional pinocytosis, in methuosis, macropinosomes neither recycle nor fuse with lysosomes but with each other to form giant vacuoles, which finally cause rupture of the plasma membrane (PM). Understanding methuosis longs for the understanding of the ionic mechanisms of cell volume regulation (CVR) and vesicular volume regulation (VVR). In nascent macropinosomes, ion channels and transporters are derived from the PM. Along trafficking from the PM to the perinuclear area, the equipment of channels and transporters of the vesicle membrane changes by retrieval, addition, and recycling from and back to the PM, causing profound changes in vesicular ion concentrations, acidification, and—most importantly—shrinkage of the macropinosome, which is indispensable for its proper targeting and cargo processing. In this review, we discuss ion and water transport mechanisms with respect to CVR and VVR and with special emphasis on pinocytosis and methuosis. We describe various aspects of the complex mutual interplay between extracellular and intracellular ions and ion gradients, the PM and vesicular membrane, phosphoinositides, monomeric G proteins and their targets, as well as the submembranous cytoskeleton. Our aim is to highlight important cellular mechanisms, components, and processes that may lead to methuotic CD upon their derangement.

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Simulated hyperglycemia impairs insulin signaling in endothelial cells through a hyperosmolar mechanism

Cited by 17 publications

References 25 publications

Water as a reactant in the differential expression of proteins in cancer

Water as a reactant in the differential expression of proteins in cancer

Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes

From Pinocytosis to Methuosis—Fluid Consumption as a Risk Factor for Cell Death

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